Recent developments in receptor tyrosine kinases targeted anticancer therapy

Raval, Samir H.; Singh, Ratn Deep; Joshi, D. V.; Patel, Hasmukh S.; Mody, Shailesh K.

doi:10.14202/vetworld.2016.80-90

Cited by 20 publications

(8 citation statements)

References 145 publications

(156 reference statements)

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“…Understanding of the disease at the molecular level has allowed identification of specific molecular targets for which drugs can be identified or engineered to inhibit [17,18]. This approach has proven to be remarkably successful, as there are now several molecular targets and FDA-approved drugs for advanced-stage NSCLC [19,20,21,22].…”

Section: Introductionmentioning

confidence: 99%

Current Status of Raf Kinase Inhibitor Protein (RKIP) in Lung Cancer: Behind RTK Signaling

Raquel-Cunha

Cardoso-Carneiro

Reis

et al. 2019

Cells

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Lung cancer is the most deadly neoplasm with the highest incidence in both genders, with non-small cell lung cancer (NSCLC) being the most frequent subtype. Somatic mutations within the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are key drivers of NSCLC progression, with EGFR inhibitors being particularly beneficial for patients carrying the so-called “EGFR-sensitizing mutations”. However, patients eventually acquire resistance to these EGFR inhibitors, and a better knowledge of other driven and targetable proteins will allow the design of increasingly accurate drugs against patients’ specific molecular aberrations. Raf kinase inhibitory protein (RKIP) is an important modulator of relevant intracellular signaling pathways, including those controlled by EGFR, such as MAPK. It has been reported that it has metastasis suppressor activity and a prognostic role in several solid tumors, including lung cancer. In the present review, the potential use of RKIP in the clinic as a prognostic biomarker and predictor of therapy response in lung cancer is addressed.

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Section: Introductionmentioning

confidence: 99%

Current Status of Raf Kinase Inhibitor Protein (RKIP) in Lung Cancer: Behind RTK Signaling

Raquel-Cunha

Cardoso-Carneiro

Reis

et al. 2019

Cells

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“…The Mitogen-Activated Protein Kinase (MAPK) pathway is a key signaling pathway involved in the physiologic regulation of cell growth, survival, differentiation, apoptosis and migration [ 1 ]. Aberrant activation of the MAPK pathway has been implicated in the pathogenesis of many human diseases, including cancer, in which MAPK activation may stem from either genetic aberrations targeting RAS , B Rapidly Accelerated Fibrosarcoma ( BRAF) , or Mitogen-activated protein kinase kinase ( MEK) directly or dysregulation of upstream acting Receptor Tyrosine Kinases (RTK) [ 2 , 3 ]. MAPK activation is finely regulated at different levels; moreover, in addition to “inter-pathway” crosstalks operating at multiple levels between MAPK and other signaling cascades (e.g.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic potential of combined BRAF/MEK blockade in BRAF-wild type preclinical tumor models

Curatolo

Cognetti

Incani

et al. 2018

J Exp Clin Cancer Res

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BackgroundMounting evidence suggests that RAF-mediated MEK activation plays a crucial role in paradox MAPK (re)activation, leading to resistance and therapeutic failure with agents hitting a single step along the MAPK cascade.MethodsWe examined the molecular and functional effects of single and combined BRAF (dabrafenib), pan-RAF (RAF265), MEK (trametinib) and EGFR/HER2 (lapatinib) inhibition, using Western Blot and conservative isobologram analysis to assess functional synergism, and explored genetic determinants of synergistic interactions. Immunoprecipitation based assays were used to detect the interaction between BRAF and CRAF. The Mann-Whitney U test was used for comparing quantitative variables.ResultsHere we demonstrated that a combination of MEK and BRAF inhibitors overcomes paradoxical MAPK activation (induced by BRAF inhibitors) in BRAF-wt/RAS-mut NSCLC and PDAC in vitro. This results in growth inhibitory synergism, both in vitro and in vivo, in the majority (65%) of the cellular models analyzed, encompassing cell lines and patient-derived cancer stem cells and organoids. However, RAS mutational status is not the sole determinant of functional synergism between RAF and MEK inhibitors, as demonstrated in KRAS isogenic tumor cell line models. Moreover, in EGFR-driven contexts, paradoxical MAPK (re)activation in response to selective BRAF inhibition was dependent on EGFR family signaling and could be offset by simultaneous EGFR/HER-2 blockade.ConclusionsOverall, our data indicate that RAF inhibition-induced paradoxical MAPK activation could be exploited for therapeutic purposes by simultaneously targeting both RAF and MEK (and potentially EGFR family members) in appropriate molecular contexts. KRAS mutation per se does not effectively predict therapeutic synergism and other biomarkers need to be developed to identify patients potentially deriving benefit from combined BRAF/MEK targeting.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0820-5) contains supplementary material, which is available to authorized users.

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“…It has been approved by State Food and Drug Administration (SFDA) and China Food and Drug Administration (CFDA) and is in phase II or III clinical trial for the treatment of patients with renal cancer, non-small cell lung cancer, and gastric cancer. Receptor tyrosine kinases (RTKs) are major novel targets in anticancer molecular therapy by blocking of the tumoral angiogenesis [3, 4]. Anlotinib is a kinase inhibitor of receptor tyrosine with multitargets, especially for vascular endothelial growth factor receptor 2 (VEGFR2), VEGFR3, platelet-derived growth factor receptor β (PDGFR β ), and c-Kit.…”

Section: Introductionmentioning

confidence: 99%

Influences of Anlotinib on Cytochrome P450 Enzymes in Rats Using a Cocktail Method

Wei

Wang

Chen

et al. 2017

BioMed Research International

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The present study aimed to investigate the effect of anlotinib (AL3818) on pharmacokinetics of cytochrome P450 (CYP) enzymes (CYP1A2, CYP2C6, CYP2D1, CYP2D2, and CYP3A1/2) by using five cocktail probe drugs in vivo. After pretreatment for 7 days with anlotinib (treatment group) or saline (control group) by oral administration, probe drugs phenacetin, tolbutamide, omeprazole, metoprolol, and midazolam were administered to rats by oral administration. Blood samples were obtained at a series of time-points and the concentrations of five probe drugs in plasma were determined by a UHPLC-MS/MS method. The results showed that treatment with anlotinib had no significant effect on rat CYP1A2, CYP2D2, and CYP2C6. However, anlotinib had a significant inductive effect on CYP2D1 and CYP3A1/2. Therefore, caution is needed during the concomitant use of anlotinib with other drugs metabolized by CYP2D1 and CYP3A1/2 because of potential drug-anlotinib interactions.

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Recent developments in receptor tyrosine kinases targeted anticancer therapy

Cited by 20 publications

References 145 publications

Current Status of Raf Kinase Inhibitor Protein (RKIP) in Lung Cancer: Behind RTK Signaling

Current Status of Raf Kinase Inhibitor Protein (RKIP) in Lung Cancer: Behind RTK Signaling

Therapeutic potential of combined BRAF/MEK blockade in BRAF-wild type preclinical tumor models

Influences of Anlotinib on Cytochrome P450 Enzymes in Rats Using a Cocktail Method

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